Alternative titles; symbols
HGNC Approved Gene Symbol: RNASEH2B
Cytogenetic location: 13q14.3 Genomic coordinates (GRCh38) : 13:50,909,678-50,970,460 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.3 | Aicardi-Goutieres syndrome 2 | 610181 | Autosomal recessive | 3 |
The RNASEH2B gene encodes the beta subunit of the human ribonuclease H2 enzyme complex which cleaves ribonucleotides from RNA:DNA duplexes. See also RNASEH2A (606034) and RNASEH2C (610330).
The RNASEH2B gene encodes a 308-amino acid protein with ubiquitous expression (Crow et al., 2006).
The RNASEH2B gene contains 11 exons (Crow et al., 2006).
The RNASEH2B gene maps to chromosome 13q14.1 (Crow et al., 2006).
By transient expression in HEK293T cells, Crow et al. (2006) showed that the human RNASEH2A, RNASEH2B, and RNASEH2C genes interact with each other and form an enzymatic protein complex with RNase H2 activity. The complex was able to recognize and cleave a single ribonucleotide embedded in a DNA-DNA complex.
By expressing fluorescence-tagged RNASEH2 subunits individually or together in HeLa cells, Kind et al. (2014) determined that the B subunit was required for nuclear expression of the A and C subunits. Mutation analysis revealed that the C terminus of the C subunit, but not a catalytically active A subunit, was also required for formation of a stable nuclear complex. Ring-shaped trimeric PCNA (176740) functions as a 'sliding clamp' along DNA that guides assembly of factors involved in DNA replication and repair. PCNA recruited RNASEH2 to sites of DNA damage, and the PIP-box motif of subunit B was required for interaction of RNASEH2 with PCNA and accumulation of RNASEH2 to sites of DNA damage. In addition, a catalytically active A subunit bound more tightly than a catalytically inactive A subunit to sites of DNA replication.
Using CRISPR screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP (173870) inhibitor, Zimmermann et al. (2018) identified a high-confidence set of 73 genes that when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, Zimmermann et al. (2018) discovered that mutations in all 3 genes encoding ribonuclease H2 (RNASEH2A, RNASEH2B, and RNASEH2C) sensitized cells to PARP inhibition and established that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase-1 (TOP1; 126420), resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. Zimmermann et al. (2018) concluded that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia may provide an opportunity to exploit these findings therapeutically.
In affected individuals from 18 unrelated families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified homozygous or compound heterozygous mutations in the RNASEH2B gene (see, e.g., 610326.0001-610326.0002). Most of the families were of European or North African descent.
Rice et al. (2007) found biallelic mutations in RNASEH2B in 47 families of 127 with a clinical diagnosis of AGS. In 1 other family an RNASEH2B mutation was found in 1 allele only. Almost all mutations were missense.
By whole-exome sequencing in 50 children with developmental disturbances of unclear etiology and with nonspecific neurologic manifestations, Mahler et al. (2019) identified 1 child with a homozygous mutation in the RNASEH2B gene (c.529G-A, A177T). The child was described as having severe global developmental delay, spastic tetraplegic cerebral palsy, and microcephaly.
In affected members of 7 families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 529G-A transition in exon 7 of the RNASEH2B gene, resulting in an ala177-to-thr (A177T) substitution. The families were of distinct nationality (Algerian, Moroccan, Irish, Italian, French Canadian, and German). Seven additional families were compound heterozygous for the A177T mutation and a different pathogenic mutation in the RNASEH2B gene (see, e.g., 610326.0002). In total, 20 of the 36 mutant alleles in 18 AGS families were A177T.
In 2 Egyptian sibs and an unrelated patient of North African descent who presented with nonsyndromic spastic paraplegia around age 2 years following normal psychomotor development, Crow et al. (2014) identified a homozygous A177T mutation in the RNASEH2B gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. None of the patients had increased interferon levels. Crow et al. (2014) emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder.
In affected members of 2 unrelated Italian families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 554T-G transversion in exon 7 of the RNASEH2B gene, resulting in a val185-to-gly (V185G) substitution. Another family of mixed European Canadian and Hungarian descent was compound heterozygous for the V185G mutation and A177T (610326.0001).
Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nature Genet. 38: 910-916, 2006. [PubMed: 16845400] [Full Text: https://doi.org/10.1038/ng1842]
Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., Gleeson, J. G., Gowrinathan, N. R., Laugel, V., Renaldo, F., Rodriguez, D., Livingston, J. H., Rice, G. I. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 45: 386-391, 2014. [PubMed: 25243380] [Full Text: https://doi.org/10.1055/s-0034-1389161]
Kind, B., Muster, B., Staroske, W., Herce, H. D., Sachse, R., Rapp, A., Schmidt, F., Koss, S., Cardoso, M. C., Lee-Kirsch, M. A. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum. Molec. Genet. 23: 5950-5960, 2014. [PubMed: 24986920] [Full Text: https://doi.org/10.1093/hmg/ddu319]
Mahler, E. A., Johannsen, J., Tsiakas, K., Kloth, K., Luttgen, S., Muhlhausen, C., Alhaddad, B., Haack, T. B., Strom, T. M., Kortum, F., Meitinger, T., Muntau, A. C., Santer, R., Kubisch, C., Lessel, D., Denecke, J., Hempel, M. Exome sequencing in children. Dtsch. Arztebl. Int. 116: 197-204, 2019. [PubMed: 31056085] [Full Text: https://doi.org/10.3238/arztebl.2019.0197]
Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 81: 713-725, 2007. [PubMed: 17846997] [Full Text: https://doi.org/10.1086/521373]
Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 559: 285-289, 2018. [PubMed: 29973717] [Full Text: https://doi.org/10.1038/s41586-018-0291-z]